Phenytoin

Base Information

• Chemical Name: Phenytoin
• CAS No.: 57-41-0
• Deprecated CAS: 125-59-7,1061190-62-2
• Molecular Formula: C15H12N2O2
• Molecular Weight: 252.272
• Hs Code.: 29332100
• European Community (EC) Number: 200-328-6,211-148-2
• NSC Number: 8722
• UN Number: 2811
• UNII: 6158TKW0C5
• DSSTox Substance ID: DTXSID8020541
• Nikkaji Number: J2.325F
• Wikipedia: Phenytoin
• Wikidata: Q410400
• NCI Thesaurus Code: C741
• RXCUI: 8183
• Pharos Ligand ID: W15HGBV8QT96
• Metabolomics Workbench ID: 42653
• ChEMBL ID: CHEMBL16
• Mol file: 57-41-0.mol

Synonyms:5,5-Diphenylhydantoin;5,5-diphenylimidazolidine-2,4-dione;Antisacer;Difenin;Dihydan;Dilantin;Diphenylhydantoin;Diphenylhydantoinate, Sodium;Epamin;Epanutin;Fenitoin;Hydantol;Phenhydan;Phenytoin;Phenytoin Sodium;Sodium Diphenylhydantoinate

Chemical Property of Phenytoin

Chemical Property:

• Appearance/Colour: white crystals or powder
• Vapor Pressure: 4.29E-08mmHg at 25°C
• Melting Point: 293-295 °C(lit.)
• Refractive Index: 1.5906 (estimate)
• Boiling Point: 428.2°C at 760 mmHg
• PKA: pKa 8.43(H2O,t =25,I=0.025) (Uncertain)
• Flash Point: 11°C
• PSA: 58.20000
• Density: 1.258 g/cm³
• LogP: 2.42720
• Storage Temp.: 2-8°C
• Solubility.: DMSO: soluble
• Water Solubility.: <0.01 g/100 mL at 19℃
• XLogP3: 2.5
• Hydrogen Bond Donor Count: 2
• Hydrogen Bond Acceptor Count: 2
• Rotatable Bond Count: 2
• Exact Mass: 252.089877630
• Heavy Atom Count: 19
• Complexity: 350
• Transport DOT Label: Poison

Purity/Quality:

98%, ^*data from raw suppliers

Phenytoin ^*data from reagent suppliers

Safty Information:

• Pictogram(s): T, Xn, F
• Hazard Codes: T,Xn,F
• Statements: 45-61-22-63-40-39/23/24/25-23/24/25-11-20/21/22
• Safety Statements: 53-45-36/37-16-7

MSDS Files:

SDS file from LookChem

Total 1 MSDS from other Authors

Useful:

• Drug Classes: Anticonvulsants
• Canonical SMILES: C1=CC=C(C=C1)C2(C(=O)NC(=O)N2)C3=CC=CC=C3
• Recent ClinicalTrials: Study on the Efficacy of Phenytoin in the Prophylaxis of Seizures of Patients With Pneumococcal Meningitis at Least 50 Yrs Old.
• Recent EU Clinical Trials: Enrichment randomized double-blind, placebo-controlled cross-over trial with PHEnytoin cream in patients with painful chronic idiopathic axonal polyNEuropathy
• Recent NIPH Clinical Trials: Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: A phase II, prospective, randomised study
• Description: Phenytoin is a first- generation antiepileptic drug (AED) known with the proprietary brand name of Epanutin? (Pfizer, Tadworth) in the UK and Dilantin? (Pfizer, New York, NY) in the USA. Phenytoin is an anticonvulsant agent and active metabolite of fosphenytoin . Phenytoin is formed from fosphenytoin by tissue phosphatases. It inhibits neuronal voltage-gated sodium channels in a voltage-dependent manner. Phenytoin reduces the neuronal firing frequency and decreases the amplitude of excitatory post-synaptic potentials (EPSPs) in electrically stimulated rat corticostriatal slices (EC50s = 42.8 and 33.5 μM, respectively). It protects against seizures induced by maximal electroshock (MES) in mice (ED50 = 10 mg/kg). Formulations containing phenytoin have been used in the treatment of tonic-clonic seizures and status epilepticus. The drug was first approved for the treatment of epilepsy by the Food and Drug Administration in 1953 and marketed by Parke-Davis as Dilantin. Its primary mechanism of action appears to block voltage-sensitive sodium channels in the brain (especially in the motor cortex), producing a delay in electrical recovery in neurons and stabilizing the threshold against hyperexcitability.
• Indications: Epilepsy Monotherapy and adjunctive therapy of focal and generalized tonic- clonic seizures. Recommendations summarized from NICE (2012) Seizure types: on referral to tertiary care (focal seizures), contraindicated (generalized tonic- clonic seizures if there are absence or myoclonic seizures or if juvenile myoclonic epilepsy is suspected, absence seizures, myoclonic seizures). Epilepsy types: on referral to tertiary care (benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, late- onset childhood occipital epilepsy), contraindicated (absence syndromes, juvenile myoclonic epilepsy, idiopathic generalized epilepsy, Dravet syndrome).
• Uses: Phenytoin has the same main effects on the heart as lidocaine. Its use is essentially limited, and it is primarily used only as an oral replacement of lidocaine for paroxysmal tachycardia that is caused particularly by intoxication of digitalis drugs. 5,5-Diphenylhydantoin has been used for phenytoin treatment. It has also been used to slow down or prevent mesoendoderm cell migration. Reduces incidence of grand mal seizures; appears to stabilize excitable membranes perhaps through effects on Na+, K+, and Ca2+ channels. A sodium channel protein inhibitor
• Biological Functions: Phenytoin is a valuable agent for the treatment of generalized tonic–clonic seizures and for the treatment of partial seizures with complex symptoms. The establishment of phenytoin (at that time known as diphenylhydantoin) in 1938 as an effective treatment for epilepsy was more than simply the introduction of another drug for treatment of seizure disorders. Until that time the only drugs that had any beneficial effects in epilepsy were the bromides and barbiturates, both classes of compounds having marked CNS depressant properties. The prevailing view among neurologists of that era was that epilepsy was the result of excessive electrical activity in the brain and it therefore seemed perfectly reasonable that CNS depressants would be effective in antagonizing the seizures. Consequently,many patients received high doses of barbiturates and spent much of their time sedated. Also, since CNS depression was considered to be the mechanism of action of AEDs, the pharmaceutical firms were evaluating only compounds with profound CNS depressant properties as potential antiepileptic agents. It was, therefore, revolutionary when phenytoin was shown to be as effective as phenobarbital in the treatment of epilepsy without any significant CNS depressant activity. This revolutionized the search for new anticonvulsant drugs as well as immediately improving the day-to-day functioning of epileptic patients. An understanding of absorption, binding, metabolism, and excretion is more important for phenytoin than it is for most drugs. Following oral administration, phenytoin absorption is slow but usually complete, and it occurs primarily in the duodenum. Phenytoin is highly bound (about 90%) to plasma proteins, primarily plasma albumin. Since several other substances can also bind to albumin, phenytoin administration can displace (and be displaced by) such agents as thyroxine, triiodothyronine, valproic acid, sulfafurazole, and salicylic acid.
• Clinical Use: Phenytoin (Dilantin) was originally introduced for the control of convulsive disorders but has now also been shown to be effective in the treatment of cardiac arrhythmias. Phenytoin appears to be particularly effective in treating ventricular arrhythmias in children. Phenytoin, like lidocaine, is more effective in the treatment of ventricular than supraventricular arrhythmias. It is particularly effective in treating ventricular arrhythmias associated with digitalis toxicity, acute myocardial infarction, open-heart surgery, anesthesia, cardiac catheterization, cardioversion, and angiographic studies. Phenytoin finds its most effective use in the treatment of supraventricular and ventricular arrhythmias associated with digitalis intoxication. The ability of phenytoin to improve digitalis-induced depression of A-V conduction is a special feature that contrasts with the actions of other antiarrhythmic agents. Phenytoin is one of very few drugs that displays zero-order (or saturation) kinetics in its metabolism.At low blood levels the rate of phenytoin metabolism is proportional to the drug’s blood 1evels (i.e., first-order kinetics). However, at the higher blood levels usually required to control seizures, the maximum capacity of drug-metabolizing enzymes is often exceeded (i.e., the enzyme is saturated), and further increases in the dose of phenytoin may lead to a disproportionate increase in the drug’s blood concentration. Since the plasma levels continue to increase in such a situation, steady-state levels are not attained, and toxicity may ensue. Calculation of half-life (t1/2) values for phenytoin often is meaningless, since the apparent half-life varies with the drug blood level. Acute adverse effects seen after phenytoin administration usually result from overdosage. They are generally characterized by nystagmus, ataxia, vertigo, and diplopia (cerebellovestibular dysfunction). Higher doses lead to altered levels of consciousness and cognitive changes. A variety of idiosyncratic reactions may be seen shortly after therapy has begun. Skin rashes, usually morbilliform in character, are most common. Exfoliative dermatitis or toxic epidermal necrolysis (Lyellís syndrome) has been observed but is infrequent. Other rashes occasionally have been reported, as have a variety of blood dyscrasias and hepatic necrosis.
• Drug interactions: Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the latter drugs inhibit the hepatic metabolism of phenytoin. A reduction in phenytoin dose can alleviate the consequences of these drug–drug interactions.

Technology Process of Phenytoin

There total 113 articles about Phenytoin which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 100.0%

ethyl 3-(5,5-diphenylhydantoin) formate (1097-57-0) → phenythoin (57-41-0)

Guidance literature:

With hydrazine hydrate; In ethanol; Heating;

Reference yield: 98.2%

benzil (134-81-6) + urea (57-13-6) → phenythoin (57-41-0)

Guidance literature:

With potassium hydroxide; In ethanol; water; at 20 ℃; for 0.05h; Sonication;

DOI:10.1002/cjoc.201090062

Reference yield: 98.0%

benzil (134-81-6) + urea (57-13-6) → 3a,6a-diphenylglycoluril (5157-15-3) + phenythoin (57-41-0)

Guidance literature:

With sodium hydroxide; for 0.0333333h; Microwave irradiation; neat (no solvent);

DOI:10.1134/S1070428009030270

upstream raw materials:

2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one

chromium(lll) acetate

4-methylsulfanyl-5,5-diphenyl-1,5-dihydro-imidazol-2-one

2,5-bis-methylsulfanyl-4,4-diphenyl-4H-imidazole

Downstream raw materials:

3-<3-Piperidino-propyl>-5.5-diphenyl-hydantoin

3-N-(2-morpholinoethyl)-5,5-diphenylhydantoin

N⁽³⁾,N'⁽³⁾-tetramethylene-bis-5,5-diphenylhydantoin

3-ethyl-5,5-diphenylhydantoin

Refernces

• 1、 Narisawa, Shinji,Stella, Valentino J.. "Increased shelf-life of fosphenytoin: Solubilization of a degradant, phenytoin, through complexation with (SBE)(7m)-β-CD". . p. 926 - 930. Retrieved 1998.
• 2、 Scriba, Gerhard K. E.,Lambert, Didier M.. "Synthesis and anticonvulsant activity of N-benzyloxycarbonyl-amino acid prodrugs of phenytoin". . p. 549 - 553. Retrieved 1999.
• 3、 Guerrab, Walid,Lgaz, Hassane,Kansiz, Sevgi,Mague, Joel T.,Dege, Necmi,Ansar,Marzouki, Riadh,Taoufik, Jamal,Ali, Ismat H.,Chung, Ill-Min,Ramli, Youssef. "Synthesis of a novel phenytoin derivative: Crystal structure, Hirshfeld surface analysis and DFT calculations". . . Retrieved 2020.
• 4、 Georgiev, Anton,Georgieva, Stela,Peneva, Petia,Rusew, Rusi,Shivachev, Boris,Todorov, Petar. "Experimental and theoretical study of bidirectional photoswitching behavior of 5,5′-diphenylhydantoin Schiff bases: Synthesis, crystal structure and kinetic approaches". . p. 15081 - 15099. Retrieved 2020/10/02.